Journal
JOURNAL OF PHARMACOLOGICAL SCIENCES
Volume 125, Issue 2, Pages 184-192Publisher
JAPANESE PHARMACOLOGICAL SOC
DOI: 10.1254/jphs.13224FP
Keywords
cardiac fibrosis; H2O2; Ca2+ signal; transient receptor potential melastatin 7 (TRPM7); extracellular signal-regulated kinase 1/2 (ERK1/2)
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Funding
- National Natural Science Foundation of China [30670837]
- NSFC-CIHR [30811120434]
- Medical Scientific Research Foundation of Guangdong Province [A2012166]
- Natural Science Foundation of Guangdong Province [S2012040006327]
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Transient receptor potential melastatin 7 (TRPM7), a Ca2+-nonselective cation channel, plays a key role in the pathophysiological response of multiple cell types. However, the role of TRPM7 channels in hydrogen peroxide (H2O2)-induced cardiac fibrosis remains unclear. This study aimed to explore whether TRPM7 channels are involved in H2O2-induced cardiac fibrosis and the underlying mechanisms. Our results showed that 2-aminoethoxydiphenylborate (2-APB), which is commonly used to block TRPM7 channels, inhibited H2O2-induced cardiac fibrosis via attenuating the overexpression of important fibrogenic biomarkers and growth factors in cardiac fibroblasts, including collagen type I (Col I), fibronectin (FN), smooth muscle alpha-actin (alpha-SMA), connective tissue growth factor (CTGF), and transforming growth factor-beta 1 (TGF-beta 1). In addition, 2-APB also decreased H2O2-mediated elevation of the concentration of intracellular Ca2+ ([Ca2+]i). Meanwhile, silencing TRPM7 channels by shRNA interference also impaired the increased [Ca2+]i and upregulation of Col I, FN, alpha-SMA, CTGF, and TGF-beta 1 induced by H2O2. Furthermore, we found that H2O2-mediated activation of extracellular signal regulated kinase 1/2 (ERK1/2) decreased in TRPM7-shRNA cells and Ca2+-free culture media. These results demonstrated that TRPM7 channels contributed to H2O2-induced cardiac fibrosis and suggested that this contribution may be through mediating Ca2+ influx and phosphorylation of ERK1/2.
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